Abstract
The generation of new neurons in the adult dentate gyrus has functional implications for hippocampal formation. Reduced hippocampal neurogenesis has been described in various animal models of hippocampal dysfunction such as dementia and depression, which are both common non-motor-symptoms of Parkinson's disease (PD). As dopamine plays an important role in regulating precursor cell proliferation, the loss of dopaminergic neurons in the substantia nigra (SN) in PD may be related to the reduced neurogenesis observed in the neurogenic regions of the adult brain: subventricular zone (SVZ) and dentate gyrus (DG). Here we examined adult hippocampal neurogenesis in the Pitx3-mutant mouse model of PD (aphakia mice), which phenotypically shows a selective embryonic degeneration of dopamine neurons within the SN and to a smaller extent in the ventral tegmental area (VTA). Proliferating cells were labeled with BrdU in aphakia mice and healthy controls from 3 to 42 weeks of age. Three weeks old mutant mice showed an 18% reduction of proliferating cells in the DG and of 26% in the SVZ. Not only proliferation but also the number of new neurons was impaired in young aphakia mice resulting in 33% less newborn cells 4 weeks after BrdU-labeling. Remarkably, however, the decline in the number of proliferating cells in the neurogenic regions vanished in older animals (8–42 weeks) indicating that aging masks the effect of dopamine depletion on adult neurogenesis. Region specific reduction in precursor cells proliferation correlated with the extent of dopaminergic degeneration in mesencephalic subregions (VTA and SN), which supports the theory of age- and region-dependent regulatory effects of dopaminergic projections. Physiological stimulation of adult neurogenesis by physical activity (wheel running) almost doubled the number of proliferating cells in the dentate gyrus of 8 weeks old aphakia mice to a number comparable to that of wild-type mice, abolishing the slight reduction of baseline neurogenesis at this age. The described age-dependent susceptibility of adult neurogenesis to PD-like dopaminergic degeneration and its responsiveness to physical activity might have implications for the understanding of the pathophysiology and treatment of non-motor symptoms in PD.
Highlights
Structural change of neuronal networks in the brain is an important mechanism for learning and memory (Shors et al, 2001)
The selective neuronal degeneration is accompanied by a robust loss of TH-positive terminals in the neurogenic region of the subventricular zone (SVZ) adjacent to the striatum but there was not such an obvious alteration in catecholaminergic innervation of the dentate gyrus (Figure 1C) likely due to remaining TH+ noradrenergic terminals in the hippocampus that originate from the locus coeruleus, which is unaffected in aphakia mice
While the movement disorder is a consequence of nigrostriatal neurodegeneration, it is not clear whether the dopaminergic deficit is responsible for non-motor symptoms
Summary
Structural change of neuronal networks in the brain is an important mechanism for learning and memory (Shors et al, 2001). Adult neurogenesis is a physiological mechanism with functional relevance for structures that benefit from an increased cell turnover: the dentate gyrus of the hippocampus and the olfactory bulb. Hoeglinger et al were the first to investigate adult neurogenesis after acute degeneration of the mesencephalic dopaminergic system using the neurotoxins MPTP and 6-hydroxydopamine (6-OHDA), respectively (Hoglinger et al, 2004). They observed significant reduction of cell proliferation in the subgranular zone of the dentate gyrus (SGZ) and the subventricular zone (SVZ), a region containing stem- and precursor cells that give rise to newborn neurons of the olfactory bulb (OB). While A9 cells predominantly innervate the striatum and the adjacent dorsal SVZ, the ventral SVZ receives dopaminergic input from A10 cells, and the SGZ of the hippocampus is innervated homogenously by A9 and A10 cells (Hoglinger et al, 2014)
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